U.S. patent number 5,543,421 [Application Number 08/327,595] was granted by the patent office on 1996-08-06 for method of treatment of peripheral neuropathies and central neurodegenerative diseases.
This patent grant is currently assigned to Synthelabo. Invention is credited to J esus Benavides, Badia Ferzaz, Pascal George, Bernard Scatton.
United States Patent |
5,543,421 |
Benavides , et al. |
August 6, 1996 |
Method of treatment of peripheral neuropathies and central
neurodegenerative diseases
Abstract
Ifenprodil and its enantiomers are disclosed for the preparation
of medicines useful for the treatment of peripheral neuropathies
and chronic neurodegenerative diseases of the central nervous
system.
Inventors: |
Benavides; J esus (Chatenay
Malabry, FR), Ferzaz; Badia (Antony, FR),
George; Pascal (Saint Arnoult en Yveline, FR),
Scatton; Bernard (Villebon sur Yvette, FR) |
Assignee: |
Synthelabo (Le Plessis
Robinson, FR)
|
Family
ID: |
9465882 |
Appl.
No.: |
08/327,595 |
Filed: |
October 24, 1994 |
Foreign Application Priority Data
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Jul 29, 1994 [FR] |
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94 09410 |
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Current U.S.
Class: |
514/317 |
Current CPC
Class: |
A61P
9/10 (20180101); A61P 25/00 (20180101); A61P
25/02 (20180101); A61K 31/445 (20130101) |
Current International
Class: |
A61K
31/445 (20060101); A61K 031/445 () |
Field of
Search: |
;514/317 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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5733 |
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Sep 1966 |
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FR |
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2678269 |
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Jun 1991 |
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FR |
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WO92/03137 |
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Mar 1992 |
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WO |
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WO95/01096 |
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Jan 1995 |
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WO |
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Other References
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Shalaby et al, "Neuroprotective effects of the N-methyl . . . ".
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J. Pharmacol Exp Ther, Feb. 1991, vol. 256, No. 2, pp. 506-512,
Sonsalla PK et al, "Competitive and noncompetitive antagonists . .
. ". .
Chemical Abstracts, vol. 120, No. 7, Feb. 1994, Abstract No.
69300m, p. 75, column 1 & p. 359, vol. 11, No. 6, "Tamura,
1991". .
J. Pharmacol. Exp. Ther., vol. 247, No. 3, 1988, pp. 1211-1221
Gotti et al, "Ifenprodil and SL82.0715 as cerabral anti-. . . ".
.
Encephale, vol. 18, No. 3, 1992, pp. 271-279, Krebs, "Acides amin
es excitateurs, une nouvelle classe de neurotransmetteurs . . . ".
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New Engl. J. Med., vol. 330, No. 9, pp. 613-622, Mar. 1994, Lipton
et al, "Mechanisms of disease: Excitatory amino acids . . . ".
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Eur. neuropsychopharmacol, 1993, vol. 3, No. 3, pp. 184-185,
Meldrum, B.S., "Anti-excitatory amino acid approach in the . . . ".
.
G. Buyuk, "Chemie f ur Pharmazeuten II", 178, Georg Thiem Verlag,
Stuttgart, pp. 29-33..
|
Primary Examiner: Cintins; Marianne M.
Assistant Examiner: Jarvis; William R. A.
Attorney, Agent or Firm: Jacobson, Price, Holman &
Stern, PLLC
Claims
We claim:
1. A method of treating peripheral neuropathies and central
neurodegenerative diseases in a patient in need thereof which
comprises administering to said patient a therapeutically effective
amount of ifenprodil or an enantiomer thereof.
2. The method of claim 1 wherein the ifenprodil or enantiomer
thereof is administered at a dose of 1 to 200 mg per day.
Description
The present invention concerns the use of ifenprodil and its
enantiomers for the preparation of medicines useful for the
treatment of peripheral neuropathies and central neurodegenerative
diseases.
Ifenprodil, or (.+-.)-erythro-1-(4-hydroxyphenyl)
2-(4-phenylmethyl-1-piperidyl)propanol, a compound with the
following structure: ##STR1## has been described together with its
vasodilator properties in U.S. Pat. No. 3,509,164.
Its cerebral anti-ischemic activity has been disclosed in J.
Pharmacol. Exp. Ther. 247, 1211 (1988) and in Brain Research 522,
290 (1990).
Ifenprodil has undergone new pharmacological studies which have
demonstrated its neurotrophic properties.
More specifically, the stimulation by ifenprodil of the
regeneration of the sciatic nerve in the rat was studied in vivo
after a local freezing lesion.
Freezing lesion destroys sciatic nerve fibres and results in a
wallerian degeneration both at the site of the lesion and in more
distal parts. This kind of lesion does not alter the nerve sheaths
allowing for reproducible nerve regeneration. The regeneration
process begins on the proximal side a few hours after the
lesion.
The rate of regeneration of sensory fibres was measured by a
pinch-test 8 days after the lesion.
Adult male rats (250 g body weight) of the Sprague-Dawley strain
were used. Rats were anaesthetized with sodium pentobarbital (60
mg/kg), the thigh skin was disinfected with ethanol and an incision
was made at the level of the junction of femoral biceps. The
sciatic nerve was approached by separating the Lateralis and Biceps
femoralis muscles. The site of the lesion was marked by a
microsuture (Black Ethilon thread 10-0) performed on perineurium
above the trifurcation of the sciatic nerve. The nerve was lesioned
by 6 freezing and thawing cycles using a copper cryode cooled in
liquid nitrogen. The wound was closed and treated with an
antibiotic (Exoseptoplix.RTM.). Animals were housed one per cage
and watched over every day.
After surgery, rats were separated into 2 experimental groups of 6
animals each:
lesioned controls receiving an ip injection of 0.1% Tween 80, 10
min, 2 h and 4 h after injury, and then twice a day for the
following seven days.
lesioned rats receiving an ip injection of 3 mg/kg of ifenprodil
tartrate (2/1) in 0.1% Tween 80, 10 min, 2 h and 4 h after injury,
and then twice a day for the following seven days.
Eight days after surgery, rats were lightly anaesthetized and the
sciatic nerve was exposed in order to carry out the pinch test.
This test consists of gently pinching the nerve with forceps every
0.5 mm starting from the most distal region from the lesion. A
reflex response (contraction of the hindlimb muscles) was observed
when pinching at the front of the regenerating sensory fibres.
After identifying this site with a microsuture, the nerve was
dissected out and the distance between the site of the lesion and
the distal microsuture was measured under a surgical microscope
using a calibrated paper. After dissection, rats were sacrificed by
a pentobarbital overdose.
In untreated lesioned animals, a response to pinch test was
observed at a distance of 26 mm from the lesion site 8 days after
surgery; this length corresponds to the distance travelled by the
regenerating sensory fibres during this time.
In rats treated with ifenprodil tartrate (2:1) at the dose of 3
mg/kg ip, the distance covered by sensory fibres was increased by
14.7%.
The results demonstrate that, in vivo, ifenprodil stimulates
peripheral nerve regeneration.
This compound can thus be used for the treatment of peripheral
neuropathies such as traumatic (nerve severing or crushing),
ischemic, metabolic (diabetes, uraemia), infectious, alcoholic,
iatrogenic, genetic neuropathies, in diseases involving motor
neurons such as spinal amyotrophies and amyotrophic lateral
sclerosis and also in the treatment of chronic neurodegenerative
diseases involving a degeneration of central nervous system axons
(Alzheimer's disease, Parkinson's disease, Multiple sclerosis).
Ifenprodil and its enantiomers can be used in any galenic form, in
association with appropriate excipients for oral, parenteral or
local administration, for example as tablets, capsules, solutions,
transdermal patches, containing 1 to 200 mg of the active substance
per unit dose, suitable for the administration of a daily dose of 1
to 200 mg of the active substance.
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